Infection of macaques with chimeric simian/human immunodeficiency viruses (SHIVs) has provided not only a model system for evaluation of vaccines and antiviral therapies, but also valuable information on HIV-1 pathogenesis. A picture is emerging whereby a common set of envelope-determined properties in vitro is closely linked to pathogenesis in viva. The envelope glycoproteins of pathogenic SHIVs confer better viral entry, increased membrane fusogenicity and resistance to neutralizing antibodies. Continued studies to assess the impact of these envelope properties on disease progression in the host as well as elucidating the mechanisms by which these envelope functions are manifested is central to our understanding of the pathogenic process of HIV infection. Furthermore, the parallel characterization of the underlying basis by which envelope glycoproteins of pathogenic CXCR4 (X4) SHIVsF33A and CCR5 (R5) SHIVsF]62P3 exert their functions in vitro provide a unique opportunity to determine whether the mechanism of pathogenesis in vivo is dependent on coreceptor usage and by extension, on distinct subpopulations of target cells. Accordingly, we propose, with combined genetic and animal infectivity studies, to correlate the in vivo pathogenic phenotypes of SAIDS-associated X4 SHIVsF33A and R5 SHIVsFI62P3 with specific in vitro envelope properties. Although increased coreceptor utilization efficiency could represent the mechanism by which viral entry as well as fusogenicity is enhanced, we hypothesize that as a result of this increase in envelope binding affinity, signal transduction through the coreceptor is also enhanced and this contributes to the replicative and cytopathic properties of pathogenic SHIVs in vivo and in vitro. We propose to test this hypothesis by assessing and comparing the binding affinity of non-pathogenic and pathogenic envelope glycoproteins to their coreceptors as well as their ability to transduce intracellular signals. We believe the studies proposed should delineate the relationship between in vitro envelope properties and in vivo pathogenic potential. Furthermore, the findings should provide insight on the mechanism for Env-mediated immunopathogenesis and the impact of coreceptor use on these mechanistic processes.